AAN.com: Can you summarize the methodology and major findings of your study?

Authors: We used clinical data of patients enrolled in the European Huntington Disease Network (EHDN) Registry to study the effect of the length of the CAG repeat in the normal HTT allele on the clinical features of Huntington disease. We found that it indeed affects the age of onset and disease progression in symptomatic patients. It is also associated with basal ganglia atrophy in asymptomatic mutation carriers. We found that the interaction between CAG repeat length in the normal and mutant allele influences the age of onset and the severity of cognitive and functional impairment: increasing CAG repeat size in the normal HTT diminishes the association between mutant CAG repeat size and disease severity.

AAN.com: What are the pathogenic implications of your findings in asymptomatic carriers?

Authors: We found that the interaction between the normal and mutant alleles influences the volume of the basal ganglia in asymptomatic carriers. This finding suggests that the interaction between normal and mutant Huntington (fragments) also has measurable effects in the preclinical stages of the disease, and thus likely represents an inherent feature of Huntington disease pathogenesis.

AAN.com: How do long CAG repeats lead to the clinical features of Huntington disease?

Authors: The number of CAG repeats in the mutant HTT allele is inversely related to age of onset in Huntington disease, accounting for up to 73 percent of the variance. Longer trinucleotide repeats correlate with an increased rate of deterioration on motor, cognitive, and functional domains, as well as weight loss, and are strongly associated with a higher rate of striatal cell loss and basal ganglia atrophy. By causing more severe pathology of the striatum, the primary site affected in Huntington disease, longer CAG repeat expansions are associated with a more severe disease course.

AAN.com: What are possible explanations for the interaction of the mutant and normal CAG repeat lengths?

Authors: There are several models that may account for our findings, including competitive polyglutamine length-dependent interaction of normal and mutant huntingtin with numerous protein binding partners, mitochondrial or extra-mitochondrial energy production, transcriptional regulation, or aggregate formation. We think that future mechanistic studies are necessary to identify the most important underlying pathways.

AAN.con: Has the association between the length of the CAG repeat sequence in the mutant and normal alleles been described in other polyglutamine diseases such as SBMA, DRPLA, and some spino-cerebellar ataxias?

Authors: In other polyglutamine diseases there is also a strong inverse association between the length of the CAG repeat mutation and the age of onset. Moreover, in some of these diseases (particularly several spinocerebellar ataxias), there are also indications that the disease has a more severe course in the homozygous gene carriers. However, to our knowledge, the potential clinical effects of the CAG repeat length in the normal allele has not been investigated in other diseases. In this regard, our findings in Huntington disease may serve as a model for similar studies in other disorders.

AAN.com: What are the implications of your findings for clinical neurologists?

Authors: We showed that the normal HTT allele can influence disease severity. Our findings suggest that Huntington disease displays an intermediate dominant phenotype in humans. This was also found in recent studies in transgenic mouse models. Our findings challenge the traditional view, found in nearly every textbook on neurology or clinical genetics, of Huntington disease as a disorder with complete dominance.

AAN.com: How will your findings help design and interpret future therapeutic trials?

Authors: Future clinical trials aimed at assessing the efficacy of a particular therapy should adjust the outcome for the effects of CAG repeat sizes in both HTT alleles: mutant and normal.

Authors: The European Huntington Disease Network (EHDN) Registry study—a multi-center, prospective, observational study—is EHDN's core study. It was established in 2004 to collect phenotypical data and biomaterials from a large group of patients with Huntington disease. The study aims to enlist one third of the European Huntington disease population by 2010. Its major goals are to obtain data on the natural history of Huntington disease, to identify genetic modifiers and biomarkers that tract disease progression, and to expedite the recruitment of participants for future clinical trials. The High Q Foundation, a non-profit organization that supports a variety of research projects seeking to find treatments for Huntington disease, sponsors the Registry study.

Author Disclosures

Mr. Aziz has received a grant from the Netherlands Organization for Scientific Research, a Dutch governmental institute for the advancement of scientific research, and from the CHDI/HighQ Foundation.

Dr. Roos has received research support from NNO, the Dutch Organization for Government Research in Huntington Disease, and from the CHDI.

Dr. Merino performed a one-time consultation with staff from Bell, Falla and Associates.